Chronic rhinosinusitis (CRS) affects nearly 30 million Americans, has direct costs of approximately $6B annually and is responsible for almost 500,000 surgeries per year. Investment in research on CRS has been modest and our knowledge of the epidemiology, genetics and pathogenesis of CRS is rudimentary. A major goal of the Chronic Rhinosinusitis Integrative Studies Program (CRISP) project is to perform highly collaborative studies to develop fundamental knowledge on the genetic polymorphisms responsible for CRS susceptibility and severity; the states, traits, environmental risk factors and costs of CRS; and the mechanisms of exacerbations and immunological basis of severe recalcitrant disease. CRISP has five main elements. Core A is the administrative Core led by Dr. Robert Schleimer, the PI of the program; Core B is the Clinical, Laboratory and Data Management Core led by Dr. Robert Kern; Project 1 studies the Epidemiology of CRS and is led by Dr. Brian Schwartz; Project 2 studies the Immunology of CRS and mechanisms of exacerbation and is led by Dr. Schleimer; and Project 3 focuses on the Genetics of CRS and is led by Dr. Carole Ober. Studies in Project 1 define the epidemiology of CRS in a large (>300,000) primary care population at Geisinger Health Systems (GHS). The Genetics studies in Project 3, based at the University of Chicago, utilize samples from 2000 patients and controls from Project 1 to identify CRS disease genes and to associate genetics with disease states, severity and environmental exposures. Candidate genes for genetic studies will be discovered via a novel systems genetics discovery platform based on collaboration between Project 3 and Project 2. A collaboration between Project 1 and Project 2, based at Northwestern University, will assess the pathogens associated with exacerbations of CRS and the role of autoimmunity in driving severe disease. Project 2 will also test the importance of B lineage cells and nasal autoimmune responses in the etiology of severe recalcitrant CRS. These collaborative studies will leverage an improved definition of sub-phenotypes of disease to identify unrecognized genetic susceptibilities and important molecular and cellular mechanisms responsible for the development and severity of CRS. RELEVANCE: The Chronic Rhinosinusitis Integrative Studies Program (CRISP) unifies and integrates three world-class research groups to understand the epidemiology, genetics and pathology of chronic rhinosinusitis. CRISP proposes highly interactive studies that leverage the population cohorts, expertise and resources of groups at Northwestern University, the University of Chicago and the Geisinger Health Systems in order to advance our understanding of chronic rhinosinusitis and point the way toward new therapeutic strategies. Project 1: CRS Epidemiology Using New Approaches to Validation in Population-based Studies Project Leader (PL): Schwartz, Brian S. DESCRIPTION (provided by applicant): CRS is disabling and is associated with high direct and indirect costs, yet little is known about the epidemiology, etiologic heterogeneity, and individual and societal burden. There is a substantial gap in understanding how to frame research needs for CRS and improve patient outcomes. This project will complete a large-scale epidemiologic study of CRS by leveraging the unique data and population assets of the Geisinger Clinic, including a primary care population of 400,000 patients in over 30 counties in Pennsylvania. We will combine longitudinal self-reported and electronic health record data with new clinical and research measurements to address gaps in understanding. While relatively little is known about the natural history of CRS, it is clear that: many patients in the general population have nasal and sinus symptoms; some of these patients are diagnosed with allergic rhinitis or episodes of ARS (symptoms for 7d to 4wk, to eliminate patients with the common cold); some of these patients progress to CRS with symptoms present for at least 12 weeks; many patients with CRS have episodes of exacerbations, with a prominent worsening of symptoms over the baseline; many patients, especially those seen in tertiary centers, have recalcitrant CRS; and the natural history must include some therapeutic and probably spontaneous remissions. The incidence, prevalence, transition rates, and risk factors for each of the steps in the framework are not well known. Since relatively little research exists in population-based samples, it is likely that most studies have focused on patients who have failed therapy, the recalcitrant group. In the proposed research, we will estimate CRS prevalence, incidence, and remission using clinically validated criteria for general population samples that represent the ful spectrum of CRS; describe patterns of CRS exacerbation and remission and the factors that explain variability; determine how CRS with and without nasal polyps cases differ from each other; evaluate a variety of community environmental risk factors for CRS using existing geospatial data on key environmental conditions; and estimate the direct and indirect costs of CRS. RELEVANCE: Chronic rhinosinusitis is a common condition that can cause severe symptoms in patients. It involves inflammation of the paranasal sinuses that results in facial pain/pressure, nasal and sinus drainage, smell loss, and nasal obstruction. Little is known however about how many people have the condition, who gets it, why they get it, and the best ways to treat it. The proposed research will address many of these issues.